Disease relevance of LU135252

• Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels [1].
• OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF) [2].
• Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ET(A) receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied [3].
• Obesity potentiated contractions in response to angiotensin II in the aorta (from 6+/-2% to 33+/-5% KCl) but not in the carotid artery (4+/-1% to 3.6+/-1% KCl), an effect that was completely prevented with LU135252 treatment (6+/-0.4% versus 33+/-5% KCl) [4].
• Long-term LU135252 treatment completely prevented this activation (13.3+/-0.3 versus 55+/-4 nmol/L, P<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity [4].

High impact information on LU135252

• Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk [5].
• LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly [2].
• RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96) [6].
• ACE activity (nmol. L His-Leu. mg protein(-1)) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an orally active ET(A) receptor antagonist [4].
• In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ET[A]) receptor antagonist, LU135252, on blood pressure, vascular structure, and function [7].

Chemical compound and disease context of LU135252

• Concomitant administration of LU135252 (ET-receptor antagonist) for the first 14 days of NE administration prevented the development of hypertrophy, without altering arterial mechanics [8].
• The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension [9].
• The VF incidence, which was higher in the l-thyroxine cardiomyopathy group, was suppressed by darusentan [10].
• RESULTS: Renal gene expression of PDGF-A and PDGF-B was neither affected by 2 or 4 weeks of hypoxia nor by concomitant treatment with LU135252 or molsidomine [11].
• The effects of the selective ET-RA antagonists LU135252 (LU13) and BSF208075 (BSF20) and of the unselective endothelin receptor (ET-R(A/B)) antagonist BSF420627 (BSF42) were additionally analyzed in 4% taurocholate-induced necrotizing pancreatitis [12].

Biological context of LU135252

• Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation [6].
• In TAC rats, ET(A) antagonism by darusentan improved both impairment of cardiac [3H]-NE-uptake and reduction of [3H]-mazindol binding sites [13].
• The treatment with LU135252 did not alter this pattern of gene expression [14].
• In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly [15].
• Darusentan led to a small but sustained reduction in 24-h BP but did not restore the endothelium-dependent vasorelaxation nor the NO-stimulated cGMP formation in GK rats [16].

Anatomical context of LU135252

• METHODS: Thirty male mongrel dogs surviving 180 min left anterior descending coronary artery balloon occlusion were randomised to: darusentan i.v. bolus-5 mg/kg 5 min before reperfusion-(group I); darusentan i.v. bolus+chronic oral-10 mg/kg/day-(group II); saline (group III) [17].
• We describe a simple, sensitive, and reproducible radioreceptor assay (RRA) for LU135252, a selective antagonist of the ETA receptor, using porcine aortic smooth muscle membranes as the acceptor and 125I-endothelin-1 as the ligand [18].
• To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6) [19].
• Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion [20].
• Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01) [21].

Associations of LU135252 with other chemical compounds

• Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P < .05) [22].
• The Ang II-induced increase in tissue ET-1 content and functional ECE activity was completely prevented by LU135252 (p<0.05) [23].
• Additional groups of rats were treated with an endothelin ET(A) receptor antagonist, LU135252, or a NO donor, molsidomine, respectively [24].
• In aged rats, darusentan treatment increased ion excretion (P < 0.05), reduced cortical gene expression of alphaENaC and alpha(1)-Na(+), K(+)-ATPase (both P < 0.05), and increased plasma aldosterone levels (P < 0.01) [25].
• In addition, more selective ET(A) receptor antagonists (ambrisentan, atrasentan, avosentan, clazosentan, darusentan, and sitaxsentan) are undergoing clinical trials [26].

Gene context of LU135252

• OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men [6].
• Pulmonary clearance of 125I-ET-1 was decreased by chronic but not acute treatment with the specific ETA receptor antagonist LU135252 [27].
• METHODS: ApoE-deficient and C57BL/6J control mice were fed for 30 weeks with normal chow or high-fat Western-type diet alone or in combination with darusentan (LU135252; 50 mg/kg/day) [28].
• CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men [6].
• Moreover, CA IV immunostaining was enhanced much later in the carotids, where darusentan did not cause regression of elastocalcinosis [29].

Analytical, diagnostic and therapeutic context of LU135252

• METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35% [2].
• CONCLUSIONS: Early administration of the ET(A) receptor antagonist darusentan does not affect the scar healing process at 6 weeks after experimental MI with reperfusion in dogs [17].
• The practical performance of this RRA was then tested in plasma samples obtained from (a) rats after a single oral administration of LU135252, (b) from coronary-ligated rats chronically treated with LU135252, and (c) in plasma and urine samples obtained from dogs during intrarenal infusion of LU135252 [18].
• In series 2, 5 min before cross-clamping, the treated group (n=7) received an intravenous bolus of LU135252 (5 mg/kg), whereas the control group (n=6) was given vehicle [30].
• CONCLUSION: Treatment with the selective ET-A receptor antagonist LU135252 accelerates recovery of renal function after isogeneic renal transplantation and attenuates cellular graft infiltration [31].

References